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Aim: to determine the impact of liver fibrosis on the prognosis of COVID and liver injury associated with the infection., Methods: retrospective multicenter study including 575 patients requiring admission for COVID-19 between January and June 2020. Fibrosis index-4 (FIB-4) was calculated within six months prior to infection and at six months post-infection., Results: baseline FIB-4 was elevated in patients who died (1.91 ± 0.95 vs 1.43 ± 0.85; p < 0.001). In addition, 17.1 % (32/187) of patients with baseline FIB-4 < 1.45 died vs 52.9 % (9/17) with FIB-4 > 3.25 (p < 0.001). In the adjusted multivariate analysis, baseline FIB-4 (OR 1.61 [95 % CI: 1.19-2.18]; p = 0.002) was independently associated with mortality. Parameters associated with liver injury, including aspartate aminotransferase (AST) (28 ± 10 vs 45 ± 56 IU/l; p < 0.001) and alanine aminotransferase (ALT) (20 ± 12 vs 38 ± 48 IU/l; p < 0.001) were significantly higher at admission compared to baseline. Furthermore, FIB-4 increased from baseline to the time of admission (1.53 ± 0.88 vs 2.55 ± 1.91; p < 0.001), and up to 6.9 % (10/145) of patients with FIB-4 < 1.45 on admission died vs 47.5 % if FIB-4 > 3.25 (58/122) (p < 0.001). In the adjusted multivariate analysis, FIB-4 on admission (OR 1.14 [95 % CI: 1.03-1.27]; p = 0.015) was independently associated with mortality. In addition, AST (42 ± 38 vs 22 ± 17 IU/l; p < 0.001) and ALT (40 ± 50 vs 20 ± 19 IU/l; p < 0.001) were significantly reduced at six months after the resolution of infection. Accordingly, FIB-4 decreased significantly (2.12 ± 1.25 vs 1.32 ± 0.57; p < 0.001) six months after the infection., Conclusion: increased FIB-4, either at baseline or at the time of admission, was associated with severity and mortality related to respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the liver damage expressed by elevated transaminases and FIB-4 levels was reversible in most of patients.

Background: Vaccine hesitancy and lack of access remain major issues in disseminating COVID-19 vaccination to liver patients globally. Factors predicting poor response to vaccination and risk of breakthrough infection are important data to target booster vaccine programs. The primary aim of the current study was to measure humoral responses to 2 doses of COVID-19 vaccine. Secondary aims included the determination of factors predicting breakthrough infection., Methods: COVID-19 vaccination and Biomarkers in cirrhosis And post-Liver Transplantation is a prospective, multicenter, observational case-control study. Participants were recruited at 4-10 weeks following first and second vaccine doses in cirrhosis [n = 325; 94% messenger RNA (mRNA) and 6% viral vaccine], autoimmune liver disease (AILD) (n = 120; 77% mRNA and 23% viral vaccine), post-liver transplant (LT) (n = 146; 96% mRNA and 3% viral vaccine), and healthy controls (n = 51; 72% mRNA, 24% viral and 4% heterologous combination). Serological end points were measured, and data regarding breakthrough SARS-CoV-2 infection were collected., Results: After adjusting by age, sex, and time of sample collection, anti-Spike IgG levels were the lowest in post-LT patients compared to cirrhosis (p < 0.0001), AILD (p < 0.0001), and control (p = 0.002). Factors predicting reduced responses included older age, Child-Turcotte-Pugh B/C, and elevated IL-6 in cirrhosis; non-mRNA vaccine in AILD; and coronary artery disease, use of mycophenolate and dysregulated B-call activating factor, and lymphotoxin-α levels in LT. Incident infection occurred in 6.6%, 10.6%, 7.4%, and 15.6% of cirrhosis, AILD, post-LT, and control, respectively. The only independent factor predicting infection in cirrhosis was low albumin level., Conclusions: LT patients present the lowest response to the SARS-CoV-2 vaccine. In cirrhosis, the reduced response is associated with older age, stage of liver disease and systemic inflammation, and breakthrough infection with low albumin level., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background & Aims: Hyperammonaemia is central in the pathogenesis of hepatic encephalopathy. It also has pleiotropic deleterious effects on several organ systems, such as immune function, sarcopenia, energy metabolism and portal hypertension. This study was performed to test the hypothesis that severity of hyperammonaemia is a risk factor for liver-related complications in clinically stable outpatients with cirrhosis., Methods: We studied 754 clinically stable outpatients with cirrhosis from 3 independent liver units. Baseline ammonia levels were corrected to the upper limit of normal (AMM-ULN) for the reference laboratory. The primary endpoint was hospitalisation with liver-related complications (a composite endpoint of bacterial infection, variceal bleeding, overt hepatic encephalopathy, or new onset or worsening of ascites). Multivariable competing risk frailty analyses using fast unified random forests were performed to predict complications and mortality. External validation was carried out using prospective data from 130 patients with cirrhosis in an independent tertiary liver centre., Results: Overall, 260 (35%) patients were hospitalised with liver-related complications. On multivariable analysis, AMM-ULN was an independent predictor of both liver-related complications (hazard ratio 2.13; 95% CI 1.89-2.40; p <0.001) and mortality (hazard ratio 1.45; 95% CI 1.20-1.76; p <0.001). The AUROC of AMM-ULN was 77.9% for 1-year liver-related complications, which is higher than traditional severity scores. Statistical differences in survival were found between high and low levels of AMM-ULN both for complications and mortality (p <0.001) using 1.4 as the optimal cut-off from the training set. AMM-ULN remained a key variable for the prediction of complications within the random forests model in the derivation cohort and upon external validation., Conclusion: Ammonia is an independent predictor of hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis and performs better than traditional prognostic scores in predicting complications., Lay Summary: We conducted a prospective cohort study evaluating the association of blood ammonia levels with the risk of adverse outcomes in 754 patients with stable cirrhosis across 3 independent liver units. We found that ammonia is a key determinant that helps to predict which patients will be hospitalised, develop liver-related complications and die; this was confirmed in an independent cohort of patients., Competing Interests: Conflicts of interest Rajiv Jalan is the inventor of OPA, which has been patented by UCL and licensed to Mallinckrodt Pharma. He is also the founder of Yaqrit Discovery, a spin out company from University College London, Hepyx Limited and Cyberliver. He had research collaborations with Yaqrit Discovery. The other authors have no conflicts of interest to declare. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: To assess whether corticosteroids improve prognosis in patients with AS-AIH, and to identify factors at therapy initiation and during therapy predictive of the response to corticosteroids., Methods: This was a retrospective cohort study including all patients with AS-AIH admitted to 13 tertiary centres from January 2002 to January 2019. The composite primary outcome was death or liver transplantation within 90 days of admission. Kaplan-Meier and Cox regression methods were used for data analysis., Results: Of 242 consecutive patients enrolled (mean age [SD] 49.7 [16.8] years), 203 received corticosteroids. Overall 90-day transplant-free survival was 61.6% (95% confidence interval [CI] 55.4-67.7). Corticosteroids reduced the risk of a poor outcome (adjusted hazard ratio [HR] 0.25; 95% CI 0.2-0.4), but this treatment failed in 30.5%. An internally validated nomogram composed of older age, MELD, encephalopathy and ascites at the initiation of corticosteroids accurately predicted the response (C-index 0.82; [95% CI 0.8-0.9]). In responders, MELD significantly improved from days 3 to 14 but remained unchanged in non-responders. MELD on day 7 with a cut-off of 25 (sensitivity 62.5%[95% CI: 47.0-75.8]; specificity 95.2% [95% CI: 89.9-97.8]) was the best univariate predictor of the response. Prolonging corticosteroids did not increase the overall infection risk (adjusted HR 0.75; 95% CI 0.3-2.1)., Conclusion: Older patients with high MELD, encephalopathy or ascites at steroid therapy initiation and during treatment are unlikely to show a favourable response and so prolonged therapy in these patients, especially if they are transplantation candidates, should be avoided., (© 2022 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background and Aims: Liver cancer stem cells (CSCs) could be involved in the carcinogenesis, recurrence, metastasis and chemoresistance of hepatocellular carcinoma (HCC). The aim of this study was to explore the role of lncRNA-H19 as a biomarker for liver cancer., Methods: LncRNA-H19 expression levels and the functional assays were conducted in EpCAM + CD133 + CSCs and C57BL/6J mice fed with a high-fat high-cholesterol carbohydrate (HFHCC) or standard diet for 52 weeks. Liver tissue and plasma samples from patients with cirrhosis, with or without HCC, were used for the analyses of gene expression and circulating lncRNA-H19 levels in an estimation and validation cohort., Results: EpCAM + CD133 + cells showed a stem cell-like phenotype, self-renewal capacity, upregulation of pluripotent gene expression and overexpressed lncRNA-H19 (p < .001). Suppression of lncRNA-H19 by antisense oligonucleotide treatment significantly reduced the self-renewal capacity (p < .001). EpCAM, CD133 and lncRNA-h19 expression increased accordingly with disease progression in HFHCC-fed mice (p < .05) and also in liver tissue from HCC patients (p = .0082). Circulating lncRNA-H19 levels were significantly increased in HCC patients in both cohorts (p = .013; p < .0001). In addition, lncRNA-H19 levels increased accordingly with BCLC staging (p < .0001) and decreased after a partial and complete therapeutic response (p < .05). In addition, patients with cirrhosis who developed HCC during follow-up showed higher lncRNA-H19 levels (p = .0025)., Conclusion: LncRNA-H19 expression was increased in CSCs, in liver tissue and plasma of patients with HCC and decreased after partial/complete therapeutic response. Those patients who developed HCC during the follow-up showed higher levels of lncRNA-H19. LncRNA-H19 could constitute a new biomarker of HCC., (© 2022 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

Background: Autoimmune hepatitis (AIH) is a chronic liver disease able to progress to acute liver failure, cirrhosis, and liver cancer. A significant proportion of patients fail to first-line therapy or develop severe toxicity., Aims: To assess safety and effectiveness of tacrolimus as a second-line therapy in AIH patients., Methods: Multicentric retrospective study of AIH patients treated with tacrolimus for at least 3 months as a second-line therapy. Effectiveness was defined as complete normalization of transaminases and IgG., Results: A total of 23 AIH patients were included in the final analysis. In 13% of patients tacrolimus was initiated because of toxicity to previous first-line treatments and the rest were switched because of previous non-efficacy. Tacrolimus was effective in 18 patients (78%; 95%CI: 55.20-91.92%). The median time receiving tacrolimus was 16 months (IQR 20). There was a sustained response with a significant improvement in all liver enzymes and IgG on last follow-up. Only one patient discontinued tacrolimus at the third month because of severe neuropathy, and ototoxicity. Responders were significantly older at diagnosis of AIH (41 ± 13 vs. 27 ± 10 years old; p = 0.0496)., Conclusion: Tacrolimus is effective and well tolerated as a second-line therapy in patients with AIH., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Hepatitis C virus (HCV) infection has been related to increased cardiovascular (CV) risk. The aim of this study was to analyze the impact of sustained virological response (SVR) on endothelial dysfunction and subclinical atherosclerosis in patients with hepatitis C virus treated with direct-acting antiviral agents., Methods: A total of 114 patients were prospectively recruited and underwent CV risk assessment including (i) endothelial dysfunction determined through laser Doppler flowmetry and (ii) subclinical atherosclerosis, elucidated by the ankle-brachial index (ABI). Atherogenic lipid profile (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides); markers of oxidative stress (oxidized low-density lipoprotein antibodies [OLAbs]), soluble markers of adhesion (vascular cell adhesion molecule [VCAM], e-selectin, and soluble markers of angiogenesis; and vascular endothelial growth factor, endothelial [EMPs] and platelet [PMPs] apoptotic microparticles, and cell-free DNA [cfDNA]) were measured. All determinations were performed at baseline, 12 weeks (SVR time), and 1 year after treatment., Results: In patients with endothelial dysfunction, area of hyperemia improved after virus clearance (P = 0.013) and was related to significant decrease in VCAM, e-selectin (P < 0.001), and cfDNA (P = 0.017) and to increased OLAb levels (P = 0.001). In patients with subclinical atherosclerosis at baseline, a significantly improved ABI was seen after HCV clearance (P < 0.001). Levels of both EMPs and PMPs also decreased after SVR and at follow-up (P = 0.006 and P = 0.002, respectively)., Discussion: HCV clearance improved not only liver function but also endothelial dysfunction and subclinical atherosclerosis promoted by decrease in levels of VCAM, e-selectin, cfDNA, and PMPs and EMPs.

Background & Aims: Information on safety and efficacy of systemic treatment in patients with hepatocellular carcinoma (HCC) under dialysis are limited due to patient exclusion from clinical trials. Thus, we aimed to evaluate the rate, prevalence, tolerability, and outcome of sorafenib in this population., Methods: We report a multicenter study comprising patients from Latin America and Europe. Patients treated with sorafenib were enrolled; demographics, dose modifications, adverse events (AEs), treatment duration, and outcome of patients undergoing dialysis were recorded., Results: As of March 2018, 6156 HCC patients were treated in 44 centres and 22 patients were concomitantly under dialysis (0.36%). The median age was 65.5 years, 40.9% had hepatitis C, 75% had Child-Pugh A, and 85% were Barcelona Clinic Liver Cancer-C. The median time to first dose modification, treatment duration and overall survival rate were 2.4 months (interquartile ranges [IQR], 0.8-3.8), 10.8 months (IQR, 4.5-16.9), and 17.5 months (95% CI, 7.2-24.5), respectively. Seventeen patients required at least 1 dose modification. The main causes of first dose modification were asthenia/worsening of Eastern Cooperative Oncology Group-Performance Status and diarrhoea. At the time of death or last follow-up, four patients were still on treatment and 18 had discontinued sorafenib: 14 were due to tumour progression, 2 were sorafenib-related, and 2 were non-sorafenib-related AE., Conclusions: The outcomes observed in this cohort seem comparable to those in the non-dialysis population. Thus, to the best of our knowledge, this is the largest and most informative dataset regarding systemic treatment outcomes in HCC patients undergoing dialysis., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: to assess the prevalence of non-alcoholic fatty liver disease (NAFLD) in the gastroenterology outpatient clinic and describe the use of the resources accordingly., Methods: a prospective and observational study of 403 patients seen in the gastroenterology outpatient clinic to rule out liver disease during three randomized months in 2016. The overall prevalence of NAFLD, disease severity, heterogeneity of the final diagnosis, the use of medical resources and their respective cost were analyzed., Results: the main reason for consultation was hypertransaminasemia (42.9%, 173/403), followed by hepatitis C virus (HCV) (28.5%, 115/403). NAFLD was identified as the definitive diagnosis in 29.8% (120/403) of the cohort, 69.2% (83/120) derived by hypertransaminasemia and 24.2% (29/120) by steatosis. Laboratory tests were performed in 96.7% (116/120), abdominal ultrasound in 88.3% (106/120), viral serology in 79.2% (95/120) and autoimmunity in 70% (84/120) of patients with NAFLD. Liver fibrosis was not assessed in 87.5% of cases. In a post-hoc analysis, 12.1% (17/120) had advanced fibrosis by FIB-4. On ultrasound, 65% (73/106) had hepatic steatosis and 15% (17/106) chronic liver disease (significant fibrosis). The mean time for diagnosis was 2.23 ± 0.8 visits. The terminology used to define the clinical diagnosis was heterogeneous as follows: a) 48.3% (58/120) hepatic steatosis; b) 15% (18/120) non-alcoholic steatohepatitis; c) 15.8% (19/120) fatty liver; d) 13.3% (16/120) metabolic syndrome; and e) 7.5% (9/120) dual liver disease (fatty liver and alcohol). A pharmacological intervention was performed in six patients, a liver biopsy in two patients and another six were referred to another specialist. The average cost per patient until diagnosis was €570.78, which included analytical, autoantibodies, viral serology and abdominal ultrasound, with a mean of 2.5 consultations. Thus, the total expense in patients with NAFLD was €68,493.6., Conclusion: NAFLD is a frequent cause of hypertransaminasemia. However, the heterogeneity in the management and terminology of the disease makes it necessary to initiate medical training actions in order to unify the criteria for disease control.

Introduction: non-alcoholic fatty liver disease is one of the most prevalent liver disorders in the developed world. Currently, there is no approved pharmacological therapy except for lifestyle intervention. Therefore, there is a need to increase the knowledge of preclinical models in order to boost novel discoveries that could lead to a better therapeutic management., Material and Methods: this study characterized the effects of two different diets, a long-term high-fat high-fructose diet (HF-HFD) and a choline-deficient, methionine supplemented high-fat diet (CDA-HFD) in C57BL/6J mice for 52 weeks or 16 weeks, respectively. Body weight, lipid and hepatic profile were analyzed and liver histology was subsequently evaluated., Results: HF-HFD animals had an increased body weight and total cholesterol levels, whereas the opposite occurred in CDA-HFD. Both HF-HFD and CDA-HFD animals had higher ALT and AST levels. With regard to histology findings, HF-HFD and CDA-HFD diets induced an increased collagen deposit and intrahepatic steatosis accumulation., Conclusion: in conclusion, the comparison of these models aided in the selection of a long-term, more physiological model for physiopathology studies or a more rapid NASH model for novel molecule testing.

Management of non-alcoholic steatohepatitis is focused on restitution of metabolic derangement, weight loss and drugs able to improve steatosis, ballooning and fibrosis. Life-style interventions based on Mediterranean diet and increasing physical activity are the first line therapy. In patients with unsuccessful life-style intervention several drugs are under development: agonist PPAR, agonist GLP-1R and agonist FXR together with drugs focussing on inflammation, ballooning, apoptosis and fibrosis. Bariatric surgery or advanced endoscopy are reserved for morbid obese without response to life-style intervention and weighting loss drugs., (Copyright © 2017 Elsevier España, S.L.U. All rights reserved.)

From the last few years, hepatitis C virus and the new direct antiviral treatments are being more and more important. In consequence, case studies like the one we present, the appearance of hepatocelullar carcinoma after its eradication with fibrosis grade 2, are getting special interest. In 2007, our patient was treated with pegylated interferon α-2a and ribavirin, having a sustained virological response after it. In this way, liver fibrosis grade 2 was confirmed by a biopsy. Finally, after corroborating a good liver functioning, the patient was discharged (as, according to the guidebooks, an ultrasound scan of screeing every 6 months was not required). In 2014, the patient came to hospital because of a pain at right hypochondrium and he was diagnosed with hepatocelullar carcinoma. A hepatectomy was done objectifying the surgical piece, liver fibrosis grade 2, one more time. Subsequently, a tumour relapse through an abdominal CT scan, a tumour relapse was found and despite the Sorafenib treatment, the patient died on January 2015. This case study provokes curiosity and uncertainty about the attitude which should be taken respect to the monitoring, and hepatocelullar carcinoma screening overall, in patients with a sustained virological response after eradicator treatment and without advanced fibrosis. Nowadays, with the benefits of the new treatments, the amount of patients in this situation is increasing significantly.

Gangliocytic paraganglioma is an uncommon tumor, which is usually located in the ampulla of Vater, and may get confused in the differential diagnosis with ampuloma or GIST. Here we present a case of a patient with upper gastrointestinal bleeding as a predominant symptom, objectified by endoscopy an ulcerative polypoid mass at the juxtapilar level, with histological result of gangliocítica paraganglioma after multiple biopsies, and finally surgical resection. The interest of this case is the difficulty for diagnosing, the different treatments and prognosis that this implies, especially for the tumor location, as surgery can lead to great complications.

Background: Colonic obstruction is a relatively common condition in emergency care, with a mortality rate of up to 20%. In 90% of cases it results from colonic or rectal adenocarcinoma, volvulus, or stenosis secondary to diverticular disease. When fecal impaction is the underlying cause, the condition is usually managed conservatively, but may on occasion become complicated and even require surgical intervention. Based on the proven efficacy of Coca-Cola® to dissolve gastric phytobezoars, we report a case of colonic obstruction secondary to sigmoid fecaloma., Case Report: A 58 years old woman arrived at the Emergency Room (ER) with persistent constipation for the last six days. An abdominal CT scan showed a large fecal mass at the sigmoid colon with retrograde dilated colonic loops. Cleansing enemas and oral lactulose were administered, which failed to resolve the clinical presentation, so we then proceeded to inject Coca-Cola® within the fecaloma using a sclerosing needle, and then washed the fecaloma surface also with Coca-Cola®. After a few minutes we started to fragment the fecalith, the consistency of which had been notably decreased., Discussion: The use of Coca-Cola® for gastric washes in the management of phytobezoars is well established. Since fecaliths are partly composed of these same substances than phytobezoars, the use of Coca-Cola® might well be warranted against them as in our patient, without surgery. Our case report is the second one published in the literature, in which Coca-Cola® helped solve colonic obstruction secondary to fecaloma.